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Cancer Therapy: Preclinical |
Levels and Transcriptional Activity: A Result of Hyperacetylation and Inhibition of Chaperone Function of Heat Shock Protein 90Authors' Affiliations: 1 Medical College of Georgia Cancer Center, Augusta, Georgia; 2 H. Lee Moffitt Cancer Center, Tampa, Florida; 3 Yale University, New Haven, Connecticut; and 4 Novartis Pharmaceuticals, Inc., Cambridge, Massachusetts
Requests for reprints: Kapil Bhalla, MCG Cancer Center, Medical College of Georgia, 1120 15th Street, CN-2101 Augusta, GA 30912. Phone: 706-721-0566; Fax: 706-721-0469; E-mail: kbhalla{at}mcg.edu.
Purpose: The molecular chaperone heat shock protein (hsp)-90 maintains estrogen receptor (ER)-
in an active conformation, allowing it to bind 17ß-estradiol (E2) and transactivate genes, including progesterone receptor (PR)-ß and the class IIB histone deacetylase HDAC6. By inhibiting HDAC6, the hydroxamic acid analogue pan-HDAC inhibitors (HA-HDI; e.g., LAQ824, LBH589, and vorinostat) induce hyperacetylation of the HDAC6 substrates
-tubulin and hsp90. Hyperacetylation of hsp90 inhibits its chaperone function, thereby depleting hsp90 client proteins. Here, we determined the effect of HA-HDIs on the levels and activity of ER
, as well as on the survival of ER
-expressing, estrogen-responsive human breast cancer MCF-7 and BT-474 cells.
Experimental Design: Following exposure to HA-HDIs, hsp90 binding, polyubiquitylation levels, and transcriptional activity of ER
, as well as apoptosis and loss of survival, were determined in MCF-7 and BT-474 cells.
Results: Treatment with HA-HDI induced hsp90 hyperacetylation, decreased its binding to ER
, and increased polyubiquitylation and depletion of ER
levels. HA-HDI treatment abrogated E2-induced estrogen response element-luciferase expression and attenuated PRß and HDAC6 levels. Exposure to HA-HDI also depleted p-Akt, Akt, c-Raf, and phospho-extracellular signal–regulated kinase-1/2 levels, inhibited growth, and sensitized ER
-positive breast cancer cells to tamoxifen.
Conclusions: These findings show that treatment with HA-HDI abrogates ER
levels and activity and could sensitize ER
-positive breast cancers to E2 depletion or ER
antagonists.
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Y. Yang, R. Rao, J. Shen, Y. Tang, W. Fiskus, J. Nechtman, P. Atadja, and K. Bhalla Role of Acetylation and Extracellular Location of Heat Shock Protein 90{alpha} in Tumor Cell Invasion Cancer Res., June 15, 2008; 68(12): 4833 - 4842. [Abstract] [Full Text] [PDF] |
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